1. Field of the Invention
The present invention relates to an anti-inflammatory agents that is useful for preventing, improving or treating inflammatory skin injuries or diseases, and skin external products and toiletries containing the same.
2. Description of the Related Art
In recent years, the causes of various skin injuries and diseases have been increasingly studied. For example, it is known that with respect to the causes of senescence, canceration, pigmentation and inflammation, inflammatory cytoklines such as IL-1xcex1 and TNF-xcex1 and extracellular matrix decomposition enzymes such as collagenase deeply participate therein (for example, xe2x80x9cOxidative Stress in Dermatologyxe2x80x9d, Marcel Dekker, Inc., pp. 187-205, 1993). The expression of genes encoding these proteins is mainly controlled at a gene transcription level. Regarding the inflammatory proteins such as inflammatory cytokines and extracellular matrix decomposition enzymes, the expression thereof is controlled by transcription control factors such as NF-xcexaB and AP-1 (for example, xe2x80x9cActive Oxygen and Signal Transferxe2x80x9d, Kodansha Scientific. pp. 37-46, 1996). Accordingly, when the expression of inflammatory proteins or the activation of transcription control factors participating therein can be inhibited, it is expected to prevent skin injuries and diseases.
For example, it is indicated that sulfur-containing antioxidants such as N-acetyl-L-cysteine and pyrrolidine dithiocarbamate inhibit NF-xcexaB activation (for example, xe2x80x9cActive Oxygen and Signal Transferxe2x80x9d, Kodansha Scientific, pp. 37-46, 1996). N-acetyl-L-cysteine is reported to inhibit also AP-1 activation (for example, FEBS Letters, vol. 384, pp. 92-96, 1996). These compounds are however problematic in the feeling upon use owing to a peculiar odor derived from a sulfur atom present in the molecular structure thereof. Besides the sulfur-containing antioxidants, AP-1 activation and expression of extracellular matrix decomposition enzymes by retinoic acid (for example, Nature, vol. 379, pp. 335-339, 1996) and inhibition of NF-xcexaB activation by a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug (for example, Bio Essays, vol. 18, pp. 371-378, 1996) have been reported. Nevertheless, retinoic acid has a side effect such as skin peeling, and a steroidal anti-inflammatory drug has a side effect such as steroidal dermatosis. Accordingly, the use thereof is limited. Although a non-steroidal anti-inflammatory drug is free from a systemic side effect encountered in the steroidal anti-inflammatory drug, a local side effect thereof has to be improved, and further, an effect of inhibiting inflammatory factor activation is unsatisfactory.
It is an object of the invention to provide an anti-inflammatory agents which inhibits expression of an Inflammatory protein and activation of a gene transcription control factor participating therein and which exhibits a good feeling upon use and a safety.
The present inventors have assiduously conducted investigations to achieve the object, and have consequently found that the object is achieved by using amino acid derivatives represented by the following formula (I) or salts thereof as an active ingredient. This finding has led to the completion of the invention.
That is, the invention relates to an anti-inflammatory agents containing, as an active ingredient, at least one selected from amino acid derivatives represented by formula (I) 
wherein
Ar represents an optionally substituted 2-hydroxyaryl group,
n is 0 or 1.
R2 represents a hydrogen atom or a side chain of an xcex1-amino acid or a xcex2-amino acid,
X represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94,
R1 represents a hydrogen atom or a group that forms, together with R2 and an adjacent atoms, a cyclic structure of pyroglutamic acid, and
R3represents a hydrogen atom, an alkyl group having from 1 to 22 carbon atoms or an alkenyl group having from 2 to 22 carbon atoms,
and salts thereof.
Further, the invention relates to an agent for preventing or treating inflammatory diseases, especially ultraviolet induction inflammatory diseases which agent contains at least one of the amino acid derivatives represented by formula (I) and the salts thereof.
Still further, the invention relates to a toiletry additive which is added as a toiletry component, this toiletry additive being composed of at least one of the amino acid derivatives represented by formula (I) and the salts thereof.
Furthermore, the invention relates to toiletries or skin external products containing at least one selected from the amino acid derivatives represented by formula (I) and the salts thereof. The toiletries of the invention are useful for preventing or improving inflammatory skin injuries, and the skin external products of the invention are useful for preventing or treating inflammatory diseases.
Of the compounds represented by formula (I), the compounds represented by formula (II) are novel compounds undescribed in the literature or publication. 
wherein
Ar may be substituted with 2-hydroxyaryl group,
m is 0 or 1,
R5 represents a side chain selected from the group of alanine, phenylalanine, serine, cysteine. aspartic acid, cysteic acid, homocysteic acid, ornithine or histidine when m is 0 and , R5 represents hydrogen atom when m is 1,
R4 represents a hydrogen atom or a group that forms, together with R5 and adjacent atoms, a cyclic structure of pyroglutamic acid, and
Y represents xe2x80x94OR6, xe2x80x94NHR6 or xe2x80x94NH2, and
R6 represents alkyl group having from 1 to 7 carbon atoms.
The present invention will be explained in detail as follows.
In the compounds represented by formula (I), n is an Integer of 0 or 1. When n is 0, the compounds represented by formula (I) are xcex2-amino acid derivatives. When n is 1, the compounds represented by formula (I) are xcex2-amino acid derivatives.
When n is 0, R2 in the amino acid derivatives represented by formula (I) is a hydrogen atom or a side chain of an xcex1-amino acid. Examples of the side chain of the xcex1-amino acid include side chain of acidic amino acids such as glutamic acid, aspartic acid, cysteic acid and homocysteic acid, neutral amino acids such as glycine, alanines valine, leucine, isoleucine, phenylalanine, tryptophan, threonine, serine, homoserine,tyrosine, dopa, cysteine, methionine, glutamine and asparagine, and basic amino acids such as lysine, ornithine, arginine and histidine. Side chains of neutral amino acids are preferable.
Further, when n is 1, R2 may be a hydrogen atom or a side chain of a xcex2-amino acid. As the xcex2-amino acid, xcex2-alanine is preferable.
In the amino acid derivatives represented by formula (I), R1 is usually a hydrogen atom. However, R1 can also form, together with R2 and an adjacent atom, a cyclic structure: As the cyclic structure, a 2-pyrrolidone ring is preferable.
In this case, the compounds represented by formula (I) are pyroglutamic acid derivatives.
When an asymmetric carbon atom is present in the amino acid residue, the compounds may be either optically active compounds or racemic compounds.
The alkyl group in R3 of formula (I) is a linear or branched alkyl group having from 1 to 22 carbon atoms, preferably from 1 to 18 carbon atoms, and it may have an unsaturated group in a part of a carbon chain. Examples of the alkyl group in the invention include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, sec-amyl, tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, cetyl, isocetyl, stearyl, isostearyl, behenyl groups and so on.
Further, the alkenyl group is a linear or branched alkenyl group having from 2 to 22 carbon atoms, preferably from 2 to 18 carbon atoms, more preferably from 5 to 18 carbon atoms which group may have at least one of carbon-carbon double bonds or carbon-carbon triple bonds as required. An alkenyl group derived from unsaturated fatty acids, such as an oleyl group, is preferable.
The 2-hydroxyaryl group in Ar group in formulae (I) and (II) is not particularly limited so long as it is an aromatic group having a hydroxyl group in the 2-position of a 5- or 6-membered aromatic ring. This aryl group is a monocyclic, polycyclic or fused-ring aromatic hydrocarbon group having at least one 6 -membered aromatic ring, or a monocyclic, polycyclic or fused-ring aromatic heterocyclic group having a 5- to 8-membered heterocyclic ring containing at least one of hetero-atoms such as nitrogen, oxygen and sulfur atoms, these groups having from 6 to 21 carbon atoms, preferably from 6 to 14 carbon atoms, more preferably from 6 to 12 carbon atoms.
These 2-hydroxyaryl groups may optionally be substituted unless it has an adverse effect on the activity of inhibiting inflammatory factor activation in the invention. At this time, examples of the substituent include the above-mentioned alkyl groups, alkoxy groups corresponding to the alkyl groups, alkoxycarbonyl groups corresponding to the alkyl groups, halogen atoms such as chlorine, fluorine and bromine, a hydroxyl group, a carboxyl group, nitro group and so on.
Specific examples of the optionally substituted 2-hydroxyaryl group of formulae (I) and (II) include 2-hydroxyphenyl, 2-hydroxy-1-naphthyl, 1-hydroxy-2-naphthyl, 2-hydroxy-4-methoxyphenyl, 2-hydroxy-3-methoxyphenyl, 5-bromo-2-hydroxyphenyl, 5-chloro-2-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, 3,5-dibromo-2-hydroxyphenyl, 3,5-dichloro-2-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl groups and so on.
In the compounds represented by formula (II), m is an integer of 0 or 1. When m is 0, the compounds represented by formula (II) are xcex1-amino acid derivatives. When m is 1, the compounds represented by formula II) are xcex2-amino acid derivatives.
When the compounds represented by formula (II) are xcex1-amino acid derivatives (that is, when m is 0), examples of the amino acid include alanine, phenylalanine, serine, cysteine, aspartic acid, cysteic acid, homocysteic acid, ornithine and histidine. In this case, the substituent R5 represents the side chain of the amino acid. When the compounds represented by formula (II) are xcex2-amino acid derivatives (that is, m is 1), the amino acid is xcex2-alanine.In this case, the substituent R5 represents a hydrogen atom.
In the compounds represented by formula (II), the substituent R4is usually a hydrogen atom. However, R4 can also form, together with R6 and an adjacent atoms, a cyclic structure.
As the cyclic structure, a 2-pyrrolidone ring is preferable.
In this case, the compounds represented by formula (II) are pyroglutamic acid derivatives.
In the compounds represented by formula (II), Y is xe2x80x94OR6, xe2x80x94NHR6 or xe2x80x94NH2 in which R6 represents an alkyl group having from 1 to 7 carbon atoms. The alkyl group having from 1 to 7 carbon atoms in R6 is a linear or branched saturated alkyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyi, sec-amyl, tert-amyl, isoamyl and n-hexyl groups.
Accordingly, xe2x80x94OR6 in the substituent Y is an alkoxy group having from 1 to 7 carbon atoms. Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, tert-amyloxy, isoamyloxy and n-hexyloxy groups.
Further, xe2x80x94NHR6 in the substituent Y is an N-alkylamino group, and it is an amino group substituted by the above-mentioned alkyl group.
Examples of the salts of the compounds represented by formulae (I) and (II) include inorganic acid salts such as a hydrochloride, a sulfate, a carbonate and a phosphate; and organic acid salts such as an acetate, a tartrate, a citrate, a p-toluenesulfonate, a glycolate, a malate, a lactate, a fatty acid salt, an acidic amino acid salt, pyroglutamate and so on. These salts may be used either singly or in combination. They may be incorporated as amino acid derivative salts, or amino acid derivative salts may be formed in a composition by incorporating amino acid derivatives and salts separately.
The amino acid derivatives represented by formula (I) can easily be formed by reacting a 2-hydroxy-aromatic aldehyde such as salicylaldehyde with an amino acid alkyl ester or an amino acid alkylamide in the presence or absence of a solvent and adding a hydrogenation agent such as sodium boron hydride to the reaction mixture.
Or it can also be formed by reacting a 2-hydroxy-aromatic aldehyde with an amino acid to form a Schiff base, adding thereto a hydrogenation agent such as sodium boron hydride to obtain an N-(2-hydroxy-aromatic-1-methylene) amino acid, and then esterifying or amidating the same.
Examples of the 2-hydroxy-aromatic aldehyde include, other than salicylaldehyde, 2-hydroxy-1-naphtoaldehyde, pyridoxal, 2-hydroxy-4-methoxybenzaldehyde, o-vanillin, 5-bromosalicylaldehyde, 5-chlorosalicylaldehyde, 5-nitrosalicylaldehyde, 3,5-dibromosalicylaldehyde, 3,5-dichlorosalicylaldehyde, 2,3-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde and so on.
The anti-inflammatory agents of the invention can be administered either orally or parenterally. It is preferable to administer the same directly to an inflammatory factor activation system. Usually, it is preferable that the inhibitor is used by being incorporated into toiletries or skin external products. For examples when the inhibitor is incorporated into toiletries as an active ingredient to prevent or improve inflammatory skin injuries, it may be added in an amount of from 0.01 to 10% by weight, preferably from 0.1 to 5% by weight. Further, when the inhibitor is incorporated into skin external products as an active ingredient for preventing or treating inflammatory diseases, it may be added in an amount of from 0.01 to 50% by weight, preferably from 0.1 to 20% by weight. When the amount is less than 0.01% by weight, the activity of inhibiting inflammatory factor activation is not satisfactorily exhibited, and it is thus undesirable When the amount exceeds 50% by weight, the feeling upon use is problematic in that a dry and hard feeling is given to the skin. Thus, it is undesirable.
When the anti-inflammatory agent of the invention is incorporated into toiletries or skin external products, components that are generally used in toiletries or skin external products can be added, other than the anti-inflammatory agent of the invention, unless the effects of the invention are impaired. Examples of the components which are generally used in toiletries or skin external products include an oily material, a surfactant, a solvent, a wetting agent, a high-molecular substance, a powder product, a dyestuff, a flavor and so on.
Examples of the oily material include oils such as animal and vegetable oils, waxes such as lanolin, hydrocarbons such as paraffin, higher alcohols such as cetanol, higher fatty acids such as stearic acid, sterols, phospholipids such as lecithin, synthetic esters such as myristic acid, metallic soaps, a silicone oil and so on.
Examples of the surfactant include an anionic surfactant, a cationic surfactant, an ampholytic surfactant, a nonionic surfactant, an emulsifying agent, a solubilizing agent and so on.
Examples of the solvent include lower alcohols such as ethanol, ethers, glycerols, liquid nonionic surfactants, liquid oily materials, other organic solvents and water.
Examples of the wetting agent include polyhydric alcohols such as glycerol, salts of organic acids such as pyrrolidonecarboxylic acid, urea, mucopolysaccharides such as hyaluronic acid, and salts of amino acids such as proline.
Examples of the high-molecular substance include natural high-molecular compounds such as collagen. semisynthetic high-molecular compounds such as a partially deacetylated chitin, and synthetic high-molecular compounds such as carboxymethyl cellulose.
Examples of the powdery product include inorganic pigments such as talc, functional pigments such as synthetic mica, hybrid fine powders, pearlessence pigments such as titanium dioxide-coated mica, photochromic pigments, high-molecular powders such as a nylon powder, and organic powders such as Nxcex5-lauroyl lysine.
Examples of the dyestuff include a legal tar dyestuff first group, a legal tar dyestuff second group, a legal tar dyestuff third group, a hairdye, a natural dyestuff and a mineral dyestuff.
Examples of the flavor include animal flavors such as musk, vegetable flavors such as a jasmine oil, synthetic flavors such as xcex1-amylcinnamaldehyde, and mixed flavors.
The form of the toiletries or the skin external products containing the anti-inflammatory agent of the invention is not particularly limited. The toiletries or the skin external products may take the form of a solution, a paste, a gel, a solid or a powder. They may be used in an oil, a lotion, a cream, a milky lotion, a gel, a shampoo, a hair rinse, a hair conditioner, an enamel, a foundation, a lipstick, a cosmetic powder, a pack, an ointment, a tablet, an injection, a granule, a capsule, a perfume, a powder, an eau de Cologne, a toothpaste, a soap, an aerosol and a cleansing foam, as well as in an agent for preventing or improving skin aging, an agent for preventing or improving skin inflammation, a bath product, a hair tonic, a skin beauty lotion, an anti-sunburn agent, an agent for preventing or improving photodermatosis such as xeroderma pigmentosum or solar urticaria, an agent for preventing or improving photoallergy, an agent for preventing or improving photo-immunosuppression and an agent for preventing or improving skin irritation by injuries, chaps or cracks. Further, they can be used as an agent for preventing or treating various diseases caused by inflammatory factor activation, for example, rheumatoid diseases such as chronic rheumatism, arthritis, cutaneous diseases such as atopic dermatitis, contact dermatitis and psoriasis vulgaris, respiratory diseases such as bronchial asthma and bronchitis, inflammatory bowel diseases, acute or chronic hepatitis, acute or chronic nephritis, Mediterranean fever, and ischemic diseases such as myocardial infarction.
Moreover, other ordinary components in toiletries or skin external products can be added to the toiletries or the skin external products containing the anti-inflammatory agent of the invention unless the effects of the invention are impaired. The other ordinary components in toiletries or skin external products include an antiseptic, a disinfectant, an antioxidant, an ultraviolet absorber, a chelating agent, a discoloration preventing agent, a buffer, a drug for an acne, an agent for preventing dandruff and itching, an antiperspirant, a burn agent, an acaricidal and louse-killing agent, a keratin softening agent, a xerosis agent, an antiviral agent, a percutaneous absorption accelerator, hormones, vitamins, amino acids, peptides, proteins, an astringent, an anti-inflammatory agent, a refrigerant, a stimulant, components derived from animals and vegetables, a melanin synthesis inhibitor (whitening agent), antibiotics, an antifungal agent and a hair tonic.
The anti-inflammatory agent of the invention has an excellent activity of inhibiting inflammatory factor activation. Further, when the toiletries or the skin external products containing the anti-inflammatory agent of the invention are coated on the skin, these effectively remain on the skin, are hard to drop and have an excellent feeling upon use.